1. Field of the Invention
This invention relates to the treatment of cancer. In particular, the invention relates to the use of inhibitors IκB kinase to inhibit the growth of a cancer cell and for the treatment of cancer, including multiple myeloma.
2. Background of the Invention
The transcription factor NF-κB is a member of the Rel protein family, and is typically a heterodimer composed of p50 and p65 subunits. NF-κB is constitutively present in the cytosol, and is inactivated by its association with one of the IκB family of inhibitors. Palombella et al., WO 95/25533, teaches that the ubiquitin-proteasome pathway plays an essential role in the regulation of NF-κB activity, being responsible both for processing of p105 to p50 and for the degradation of the inhibitor protein IκBα. Chen et al., Cell 84:853 (1996), teaches that prior to degradation, IκBα undergoes selective phosphorylation at serine residues 32 and 36 by the multisubunit IκB kinase complex (IKK). Once phosphorylated, IκB is targeted for ubiquitination and degradation by the 26S proteasome, allowing translocation of NF-κB into the nucleus, where it binds to specific DNA sequences in the promoters of target genes and stimulates their transcription.
Ritzeler et al., WO 01/68648, discloses a series of beta-carboline compounds with IκB kinase inhibitory activity. Rinehart et al., U.S. Pat. No. 4,631,149, discloses beta-carboline compounds useful as antiviral, antibacterial, and antitumor agents.
The protein products of genes under the regulatory control of NF-κB include cytokines, chemokines, cell adhesion molecules, and proteins mediating cellular growth and control. Importantly, many of these proinflammatory proteins also are able to act, either in an autocrine or paracrine fashion, to further stimulate NF-κB activation. In addition, NF-κB plays an important role in the growth of normal and malignant cells. Baldwin, J. Clin. Invest., 107:241 (2001), teaches that NF-κB promotes cell growth by upregulating cyclin D transcription, with associated hyperphosphorylation of Rb, G1 to S-phase transition, and inhibition of apoptosis. Bargou et al., J. Clin. Invest., 100:2961 (1997), teaches that NF-κB is constitutively activated in Hodgkin's disease, and inhibition of NF-κB blocks growth of these lymphoma cells. Furthermore, Mayo et al., Science 178:1812 (1997), teaches that inhibition of NF-κB via expression of the super-repressor of IκBα induces apoptosis in cells expressing the oncogenic allele of H-Ras.
Read et al., Immunity 2:493-506 (1995), teaches that proteasome-mediated activation of NF-κB is required for expression of cell adhesion molecules, such as E-selectin, ICAM-1, and VCAM-1. Zetter, Seminars in Cancer Biology 4:219-229 (1993), teaches that cell adhesion molecules are involved in tumor metastasis and angiogenesis in vivo, by directing the adhesion and extravastation of tumor cells to and from the vasculature to distant tissue sites within the body. Moreover, Beg and Baltimore, Science 274:782 (1996), teaches that NF-κB is an anti-apoptotic controlling factor, and that inhibition of NP-κB activation makes cells more sensitive to environmental stress and cytotoxic agents.
Multiple myeloma is a B-cell malignancy of the plasma cells. It represents the second most common hematological malignancy, with non-Hodgkin's lymphoma being the most common. The annual incidence in the United States (US) is about four per 100,000, and rates in northern Europe are similar to the US. Greenlee et al., CA Cancer J Clin 50:7-33 (2000) discloses that approximately 13,600 cases of multiple myeloma are diagnosed each year with ˜11,200 deaths per year due to the disease, representing ˜2% of all cancer deaths. Multiple myeloma is one of only three cancer types to show increased mortality rates for both men and women (increases of 5.6 and 3.8%, respectively) during the period 1991-1995.
Multiple myeloma results from the clonal proliferation of plasma cells arising in the lymph nodes and “homing” to the bone marrow where these cells localize and proliferate. The disease is characterized by marrow plasma cell tumors and overproduction of a patient-specific intact monoclonal immunoglobulin heavy and/or light chain (paraprotein or M-protein). Plasma cell tumors produce immunoglobulin G (IgG) in about 53% of myeloma patients and immunoglobulin A (IgA) in about 25%; 40% of these IgG and IgA patients also have Bence Jones proteinuria. Light chain myeloma is found in 15 to 20% of patients; their plasma cells secrete only free monoclonal light chains (κ or λ Bence Jones protein), and serum M-components are usually absent on electrophoresis. Immunoglobulin D (IgD) myeloma accounts for about 1% of cases. Only a few cases of immunoglobulin E (IgE) myeloma have been reported. The production of an easily detectable paraprotein in the blood and/or urine is a convenient marker for the tumor burden in most of these patients.
Multiple myeloma, unless successfully treated, leads to progressive morbidity and eventual mortality by lowering resistance to infection and causing significant skeletal destruction (with bone pain, pathological fractures, and hypercalcemia), anemia, renal failure, and, less commonly, neurological complications and hyperviscosity. Anderson et al., Semin. Hematol. 36:3 (1999), teaches that patients may initially respond to cytotoxic chemotherapy and/or steroids, but they ultimately suffer from resistant disease. This cancer remains incurable. Raje and Anderson, New Eng J Med 341:1606-1609 (1999) states that the five-year survival rate for patients with multiple myeloma has remained at 29% “for more than four decades”.
Vidriales M B and Anderson K C, Molec. Med. Today 2(1):425-431 (1996), suggests that there are complex controls on the growth of the myeloma tumor cell mass in the bone marrow, with influences from the microenvironment of the bone marrow and the production of cytokines by the malignant cell and bone marrow stromal cells. IL-6 is a critical growth factor for the myeloma cell and also inhibits apoptosis in myeloma cells. Chauhan et al., Blood, 87:1104 (1996), teaches that adhesion of myeloma cells to the bone marrow stromal cells (BMSCs) induces NF-κB dependent upregulation of IL-6 transcription and perpetuates further myeloma cell proliferation. Furthermore, Hideshima et al., Oncogene 20:4519 (2001), teaches that multiple myeloma cells secrete TNFα, which induces activation of NF-κB in BMSCs, and thereby directly upregulates IL-6 transcription and secretion in BMSCs. The reference also teaches that TNFα-induced NF-κB activation results in upregulation of ICAM-1 (CD54) and VCAM-1 (CD106) expression on both MM cells and BMSCs, resulting in an increase in MM-BMSC binding. Consistent with the role for NF-κB in multiple myeloma suggested by these references, Feinman R et al., Blood 93:3044 (1999) teaches that elevated levels of NF-κB activity are found in relapsing multiple myeloma.
Thus, there remains a need to identify inhibitors of NF-κB that are effective for the treatment of cancer, including multiple myeloma.